tbuckley/cabot-search huggingface dataset:
Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons
Authors: Margarida Beatriz, Ricardo J. Rodrigues, Rita Vilaça, Conceição Egas, Paulo S. Pinheiro, George Q. Daley, Thorsten M. Schlaeger, Nuno Raimundo, A. Cristina Rego, Carla Lopes
Journal: Theranostics (2023)

Background: Extracellular vesicles (EVs) carry bioactive molecules associated with various biological processes, including miRNAs.In both Huntington's disease (HD) models and human samples, altered expression of miRNAs involved in synapse regulation was reported.Recently, the use of EV cargo to reverse phenotypic alterations in disease models with synaptopathy as the end result of the pathophysiological cascade has become an interesting possibility.Methods: Here, we assessed the contribution of EVs to GABAergic synaptic alterations using a human HD model and studied the miRNA content of isolated EVs.Results: After differentiating human induced pluripotent stem cells into electrophysiologically active striatal-like GABAergic neurons, we found that HD-derived neurons displayed reduced density of inhibitory synapse markers and GABA receptor-mediated ionotropic signaling.Treatment with EVs secreted by control (CTR) fibroblasts reversed the deficits in GABAergic synaptic transmission and increased the density of inhibitory synapses in HD-derived neuron cultures, while EVs from HD-derived fibroblasts had the opposite effects on CTR-derived neurons.Moreover, analysis of miRNAs from purified EVs identified a set of differentially expressed miRNAs between manifest HD, premanifest, and CTR lines with predicted synaptic targets. Conclusion:The EV-mediated reversal of the abnormal GABAergic phenotype in HD-derived neurons reinforces the potential role of EV-miRNAs on synapse regulation.
New insights into the role of adipocytes in pancreatic cancer progression: paving the way towards novel therapeutic targets
Authors: Yu-Chun Lin, Ya-Chin Hou, Hao-Chen Wang, Yan-Shen Shan
Journal: Theranostics (2023)

Pancreatic cancer (PC) remains one of the most lethal malignancies across the world, which is due to delayed diagnosis and resistance to current therapies.The interactions between pancreatic tumor cells and their tumor microenvironment (TME) allow cancer cells to escape from anti-cancer therapies, leading to difficulties in treating PC.With endocrine function and lipid storage capacity, adipose tissue can maintain energy homeostasis.Direct or indirect interaction between adipocytes and PC cells leads to adipocyte dysfunction characterized by morphological change, fat loss, abnormal adipokine secretion, and fibroblast-like transformation.Various adipokines released from dysfunctional adipocytes have been reported to promote proliferation, invasion, metastasis, stemness, and chemoresistance of PC cells via different mechanisms.Additional lipid outflow from adipocytes can be taken into the TME and thus alter the metabolism in PC cells and surrounding stromal cells.Besides, the trans-differentiation potential enables adipocytes to turn into various cell types, which may give rise to an inflammatory response as well as extracellular matrix reorganization to modulate tumor burden.Understanding the molecular basis behind the protumor functions of adipocytes in PC may offer new therapeutic targets.
Ascorbic acid induces MLC2v protein expression and promotes ventricular-like cardiomyocyte subtype in human induced pluripotent stem cells derived cardiomyocytes
Authors: Yu Gao, Liping Su, Yuhua Wei, Shihua Tan, Zhenyu Hu, Zhonghao Tao, Jean-Paul Kovalik, Tuck Wah Soong, Jianyi Zhang, Jun Pu, Lei Ye
Journal: Theranostics (2023)

Introduction:The potentially unlimited number of cardiomyocyte (CMs) derived from human induced pluripotent stem cells (hiPSCs) in vitro facilitates high throughput applications like cell transplantation for myocardial repair, disease modelling, and cardiotoxicity testing during drug development.Despite promising progress in these areas, a major disadvantage that limits the use of hiPSC derived CMs (hiPSC-CMs) is their immaturity.Methods: Three hiPSC lines (PCBC-hiPSC, DP3-hiPSCs, and MLC2v-mEGFP hiPSC) were differentiated into CMs (PCBC-CMs, DP3-CMs, and MLC2v-CMs, respectively) with or without retinoic acid (RA).hiPSC-CMs were either maintained up to day 30 of contraction (D30C), or D60C, or purified using lactate acid and used for experiments.Purified hiPSC-CMs were cultured in basal maturation medium (BMM) or BMM supplemented with ascorbic acid (AA) for 14 days.The AA treated and non-treated hiPSC-CMs were characterized for sarcomeric proteins (MLC2v, TNNI3, and MYH7), ion channel proteins (Kir2.1,Nav1.5, Cav1.2, SERCA2a, and RyR), mitochondrial membrane potential, metabolomics, and action potential.Bobcat339, a selective and potent inhibitor of DNA demethylation, was used to determine whether AA promoted hiPSC-CM maturation through modulating DNA demethylation.Results: AA significantly increased MLC2v expression in PCBC-CMs, DP3-CMs, MLC2v-CMs, and RA induced atrial-like PCBC-CMs.AA treatment significantly increased mitochondrial mass, membrane potential, and amino acid and fatty acid metabolism in PCBC-CMs.Patch clamp studies showed that AA treatment induced PCBC-CMs and DP3-CMs adaptation to a ventricular-like phenotype.Bobcat339 inhibited MLC2v protein expression in AA treated PCBC-CMs and DP3-CMs.DNA demethylation inhibition was also associated with reduced TET1 and TET2 protein expressions and reduced accumulation of the oxidative product, 5 hmC, in both PCBC-CMs and DP3-CMs, in the presence of AA.Conclusions: Ascorbic acid induced MLC2v protein expression and promoted ventricular-like CM subtype in hiPSC-CMs.The effect of AA on hiPSC-CM was attenuated with inhibition of TET1/TET2 mediated DNA demethylation.
Macrophage promotes fibroblast activation and kidney fibrosis by assembling a vitronectin-enriched microenvironment
Authors: Yiling Peng, Li Li, Jingyue Shang, Haili Zhu, Jinlin Liao, Xue Hong, Fan Fan Hou, Haiyan Fu, Youhua Liu
Journal: Theranostics (2023)

Background: Renal infiltration of inflammatory cells including macrophages is a crucial event in kidney fibrogenesis.However, how macrophage regulates fibroblast activation in the fibrotic kidney remains elusive.In this study, we show that macrophages promoted fibroblast activation by assembling a vitronectin (Vtn)-enriched, extracellular microenvironment.Methods: We prepared decellularized kidney tissue scaffold (KTS) from normal and fibrotic kidney after unilateral ischemia-reperfusion injury (UIRI) and carried out an unbiased quantitative proteomics analysis.NRK-49F cells were seeded on macrophage-derived extracellular matrix (ECM) scaffold.Genetic Vtn knockout (Vtn-/-) mice and chronic kidney disease (CKD) model with overexpression of Vtn were used to corroborate a role of Vtn/integrin αvβ5/Src in kidney fibrosis.Results: Vtn was identified as one of the most upregulated proteins in the decellularized kidney tissue scaffold from fibrotic kidney by mass spectrometry.Furthermore, Vtn was upregulated in the kidney of mouse models of CKD and primarily expressed and secreted by activated macrophages.Urinary Vtn levels were elevated in CKD patients and inversely correlated with kidney function.Genetic ablation or knockdown of Vtn protected mice from developing kidney fibrosis after injury.Conversely, overexpression of Vtn exacerbated renal fibrotic lesions and aggravated renal insufficiency.We found that macrophage-derived, Vtn-enriched extracellular matrix scaffold promoted fibroblast activation and proliferation.In vitro, Vtn triggered fibroblast activation by stimulating integrin αvβ5 and Src kinase signaling.Either blockade of αvβ5 with neutralizing antibody or pharmacological inhibition of Src by Saracatinib abolished Vtn-induced fibroblast activation.Moreover, Saracatinib dose-dependently ameliorated Vtn-induced kidney fibrosis in vivo.These results demonstrate that macrophage induces fibroblast activation by assembling a Vtn-enriched extracellular microenvironment, which triggers integrin αvβ5 and Src kinase signaling.Conclusion: Our findings uncover a novel mechanism by which macrophages contribute to kidney fibrosis via assembling a Vtn-enriched extracellular niche and suggest that disrupting fibrogenic microenvironment could be a therapeutic strategy for fibrotic CKD.
Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes
Authors: Shuya Du, Xiaojin Zhang, Yunxiao Jia, Peipei Peng, Qiuyue Kong, Surong Jiang, Yuehua Li, Chuanfu Li, Zhengnian Ding, Li Liu
Journal: Theranostics (2023)

Rationale: Liver ischemia-reperfusion (LI/R) injury is characterized by two interconnected phases: local ischemia that causes hepatic cell damage to release damage-associated molecular pattern (DAMPs), and DAMPs that recruit immune cells to elicit inflammatory cascade for further injury of hepatocytes.High-mobility group box 1 (HMGB1) is a representative DAMP.Studies in macrophages demonstrated that HMGB1 is secreted after lactylation during sepsis.However, whether lactylation mediates HMGB1 secretion from hepatocytes after LI/R is known.Heat shock protein A12A (HSPA12A) is an atypical member of HSP70 family.Methods: Gene expression was examined by microarray analysis and immunoblotting.The hepatic injury was analyzed using released ALT and AST activities assays.Hepatic macrophage chemotaxis was evaluated by Transwell chemotaxis assays.Inflammatory mediators were evaluated by immunoblotting.HMGB1 secretion was examined in exosomes or serum.HMGB1 lactylation was determined using immunoprecipitation and immunoblotting.Results: Here, we report that LI/R decreased HSPA12A expression in hepatocytes, while hepatocyte-specific HSPA12A overexpression attenuated LI/R-induced hepatic dysfunction and mortality of mice.We also noticed that hepatocyte HSPA12A overexpression suppressed macrophage chemotaxis to LI/R-exposed livers in vivo and to hypoxia/reoxygenation (H/R)-exposed hepatocytes in vitro.The LI/R-increased serum HMGB1 levels of mice and the H/R-increased HMGB1 lactylation and secretion levels of hepatocytes were also inhibited by hepatocyte HSPA12A overexpression.By contrast, HSPA12A knockout in hepatocytes promoted not only H/R-induced HMGB1 lactylation and secretion of hepatocytes but also the effects of H/R-hepatocytes on macrophage chemotaxis and inflammatory activation, while all these deleterious effects of HSPA12A knockout were reversed following hepatocyte HMGB1 knockdown.Further molecular analyses showed that HSPA12A overexpression reduced glycolysis-generated lactate, thus decreasing HMGB1 lactylation and secretion from hepatocytes, thereby inhibiting not only macrophage chemotaxis but also the subsequent inflammatory cascade, which ultimately protecting against LI/R injury. Ivyspring
SDC1-TGM2-FLOT1-BHMT complex determines radiosensitivity of glioblastoma by influencing the fusion of autophagosomes with lysosomes
Authors: Liang Zeng, Wang Zheng, Xinglong Liu, Yuchuan Zhou, Xiaoya Jin, Yuqi Xiao, Yang Bai, Yan Pan, Jianghong Zhang, Chunlin Shao
Journal: Theranostics (2023)

Rationale: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults.Radiotherapy has long been an important treatment for GBM.Despite recent advances in tumor radiotherapy, the prognosis of GBM remains poor due to radioresistance.Autophagy has been reported as a basic factor to prolong the survival of tumor under radiation stress, but the molecular mechanism of how autophagy contributes to GBM radioresistance was still lacking.Methods: We established radioresistant GBM cells and identified their protein profiles by Tandem mass tag (TMT) quantitative proteomic analysis, then chose the radioresistant genes based on the TMT analysis of GBM cells and differentially expressed genes (DEGs) analysis of GEO database.Colony formation, flow cytometry, qPCR, western blotting, mRFP-GFP-LC3, transmission electron microscopy, immunofluorescence, and co-IP assays were conducted to investigate the regulation mechanisms among these new-found molecules.Results: Syndecan 1 (SDC1) and Transglutaminase 2 (TGM2) were both overexpressed in the radioresistant GBM cells and tissues, contributing to the dismal prognosis of radiotherapy.Mechanically, after irradiation, SDC1 carried TGM2 from cell membrane into cytoplasm, and transported to lysosomes by binding to flotillin 1 (FLOT1), then TGM2 recognized the betaine homocysteine methyltransferase (BHMT) on autophagosomes to coordinate the encounter between autophagosomes and lysosomes.Conclusions: The SDC1-TGM2-FLOT1-BHMT copolymer, a novel member of the protein complexes involved in the fusion of lysosomes and autophagosomes, maintained the autophagic flux in the irradiated tumor cells and ultimately enhanced radioresistance of GBM, which provides new insights of the molecular mechanism and therapeutic targets of radioresistant GBM.
Single-cell RNA sequencing identifies critical transcription factors of tumor cell invasion induced by hypoxia microenvironment in glioblastoma
Authors: Yanru Zhang, Bo Zhang, Chengqian Lv, Nan Zhang, Kaiyuan Xing, Zixuan Wang, Rongkai Lv, Mingchen Yu, Chaohan Xu, Yihan Wang
Journal: Theranostics (2023)

Glioblastoma (GBM) is an aggressive malignant primary brain cancer with poor survival. Hypoxia is a hallmark of GBM, which promotes tumor cells spreading (invasion) into the healthy brain tissue.
Sufu limits sepsis-induced lung inflammation via regulating phase separation of TRAF6
Authors: Yehua Li, Jiayin Peng, Yuanxin Xia, Chenyu Pan, Yu Li, Weijie Gu, Jia Wang, Chaoxiong Wang, Yuang Wang, Jiawen Song, Xuan Zhou, Liya Ma, Yiao Jiang, Biao Liu, Qiongni Feng, Wenjia Wang, Shi Jiao, Liwei An, Dianfan Li, Zhaocai Zhou, Yun Zhao
Journal: Theranostics (2023)

Rationale: Sepsis is a potentially life-threatening condition caused by the body's response to a severe infection.Although the identification of multiple pathways involved in inflammation, tissue damage and aberrant healing during sepsis, there remain unmet needs for the development of new therapeutic strategies essential to prevent the reoccurrence of infection and organ injuries.Methods: Expression of Suppressor of Fused (Sufu) was evaluated by qRT-PCR, western blotting, and immunofluorescence in murine lung and peritoneal macrophages.The significance of Sufu expression in prognosis was assessed by Kaplan-Meier survival analysis.The GFP-TRAF6-expressing stable cell line (GFP-TRAF6 Blue cells) were constructed to evaluate phase separation of TRAF6.Phase separation of TRAF6 and the roles of Sufu in repressing TRAF6 droplet aggregation were analyzed by co-immunoprecipitation, immunofluorescence, Native-PAGE, FRAP and in vitro assays using purified proteins.The effects of Sufu on sepsis-induced lung inflammation were evaluated by cell function assays, LPS-induced septic shock model and polymicrobial sepsis-CLP mice model.Results: We found that Sufu expression is reduced in early response to lipopolysaccharide (LPS)-induced acute inflammation in murine lung and peritoneal macrophages.Deletion of Sufu aggravated LPS-induced and CLP (cecal ligation puncture)-induced lung injury and lethality in mice, and augmented LPS-induced proinflammatory gene expression in cultured macrophages.In addition, we identified the role of Sufu as a negative regulator of the Toll-Like Receptor (TLR)-triggered inflammatory response.We further demonstrated that Sufu directly interacts with TRAF6, thereby preventing oligomerization and autoubiquitination of TRAF6.Importantly, TRAF6 underwent phase separation during LPS-induced inflammation, which is essential for subsequent ubiquitination activation and NF-κB activity.Sufu inhibits the phase-separated TRAF6 droplet formation, preventing NF-κB activation upon LPS stimulation.In a septic shock model, TRAF6 depletion rescued the augmented inflammatory phenotype in mice with myeloid cell-specific deletion of Sufu.Conclusions: These findings implicated Sufu as an important inhibitor of TRAF6 in sepsis and suggest that therapeutics targeting Sufu-TRAF6 may greatly benefit the treatment of sepsis.
The HDAC10 instructs macrophage M2 program via deacetylation of STAT3 and promotes allergic airway inflammation
Authors: Yu Zhong, Tong Huang, Jiewen Huang, Jingyun Quan, Guomei Su, Zhilin Xiong, Yingying Lv, Shihai Li, Xianwen Lai, Yuanyuan Xiang, Qu Wang, Lianxiang Luo, Xiao Gao, Yiming Shao, Jing Tang, Tianwen Lai
Journal: Theranostics (2023)

Background: Perturbation of macrophage homeostasis is one of the key mechanisms of airway inflammation in asthma.However, the exact mechanisms remain poorly understood.Objectives: We sought to examine the role of histone deacetylase (HDAC) 10 as an epigenetic regulator that governs macrophage M2 program and promotes airway inflammation in asthma, and to elucidate the underlying mechanisms.Methods: Peripheral blood and airway biopsies were obtained from healthy individuals and asthmatic patients.Asthma was induced by exposure to allergen in mice with myeloid-specific deletion of Hdac10 (Hdac10 fl/fl -LysMCre) mice.HDAC10 inhibitor Salvianolic acid B (SAB), STAT3 selective agonist Colivelin, and the specific PI3K/Akt activator 1,3-Dicaffeoylquinic acid (DA) were also used in asthmatic mice.For cell studies, THP1 cells, primary mouse bone marrow derived macrophage (BMDMs) were used and related signaling pathways was investigated.Results: HDAC10 expression was highly expressed by macrophages and promoted M2 macrophage activation and airway inflammation in asthmatic patients and mice.Hdac10 fl/fl -LysMCre mice were protected from airway inflammation in experimental asthma model.Hdac10 deficiency significantly attenuated STAT3 expression and decreased M2 macrophage polarization following allergen exposure.Mechanistically, HDAC10 directly binds STAT3 for deacetylation in macrophages, by which it promotes STAT3 expression and activates the macrophage M2 program.Importantly, we identified SAB as a HDAC10 inhibitor that had protective effects against airway inflammation in mice.Conclusions: Our results revealed that HDAC10-STAT3 interaction governs macrophage polarization to promote airway inflammation in asthma, implicating HDAC10 as a therapeutic target.
Facial naevus count in the identification of patients at higher risk of melanoma
Authors: Roberta Giuffrida, Gustavo Zanin Poletto, Fabrizio Guarneri, Claudio Conforti, Claudio Guarneri, Rainer Hofmann-Wellenhof, Iris Zalaudek
Journal: British Journal of Dermatology (2023)

A high total body naevus count (TBNC) is a major risk factor for melanoma. The aim of our study was to investigate the correlation between the number of facial naevi and TBNC, and how the patient variables could influence this association. Our findings suggest that facial naevus count is a fast, easy and economical tool to identify individuals with a high TBNC and may be useful as screening method for physicians in all medical fields.
Boost of innate immunity cytokines as biomarkers of response to extracorporeal photopheresis in patients with leukaemic cutaneous T-cell lymphoma
Authors: Yi-Chien Tsai, Tanja Schlaepfer, Desislava Ignatova, Yun-Tsan Chang, Alan Valaperti, Boyko Amarov, Gabriela Blanchard, Kevin Pehr, Maya Vonow-Eisenring, Mirjana Urosevic-Maiwald, Wolfram Hoetzenecker, Steve Pascolo, Christoph Iselin, Christina  Fassnacht, Florentia Dimitriou, Malgorzata Bobrowicz, Emmanuella Guenova
Journal: British Journal of Dermatology (2023)

Abstract Background Extracorporeal photopheresis (ECP) has emerged as a systemic first-line immunomodulatory therapy in leukaemic cutaneous T-cell lymphoma (L-CTCL) and is now beginning to be utilized in other T-cell-mediated diseases. Although ECP has been used for nearly 30 years, its mechanisms of action are not sufficiently understood, and biomarkers for response are scarce. Objectives We aimed to investigate the immunomodulatory effects of ECP on cytokine secretion patterns in patients with L-CTCL, to help elucidate its mechanism of action. Methods A total of 25 patients with L-CTCL and 15 healthy donors (HDs) were enrolled in this retrospective cohort study. Concentrations of 22 cytokines were simultaneously quantified by using multiplex bead-based immunoassays. Neoplastic cells in patients’ blood were evaluated by flow cytometry. Results Firstly, we observed a distinct cytokine profile pattern difference between L-CTCLs and HDs. There was a significant loss of tumour necrosis factor (TNF)-α, and significant increase of interleukins (IL)-9, IL-12 and IL-13 in the sera of patients with L-CTCL compared with HDs. Secondly, patients with L-CTCL who received ECP were classified as treatment responders and nonresponders according to the quantitative reduction of malignant burden in their blood. We evaluated cytokine levels in culture supernatants from patients’ peripheral blood mononuclear cells (PBMCs) at baseline and 27 weeks after ECP initiation. Strikingly, PBMCs purified from ECP responders released statistically higher concentrations of innate immune cytokines IL-1α, IL-1β, granulocyte–macrophage colony-stimulating factor (GM-CSF) and TNF-α in comparison with ECP nonresponders. In parallel, responders showed clearance of erythema, reduction of malignant clonal T cells in the blood, and a potent boost of relevant innate immune cytokines in individual patients with L-CTCL. Conclusions Taken together, our results demonstrate that ECP stimulates the innate immune network, and facilitates redirection of the tumour-biased immunosuppressive microenvironment towards proactive antitumour immune responses. The alterations of IL-1α, IL-1β, GM-CSF and TNF-α can be used as biomarkers of response to ECP in patients with L-CTCL.
An ensemble deep learning model for risk stratification of invasive lung adenocarcinoma using thin-slice CT
Authors: Jing Zhou, Bin Hu, Wei Feng, Zhang Zhang, Xiaotong Fu, Handie Shao, Hansheng Wang, Longyu Jin, Siyuan Ai, Ying Ji
Journal: npj Digital Medicine (2023)

Lung cancer screening using computed tomography (CT) has increased the detection rate of small pulmonary nodules and early-stage lung adenocarcinoma. It would be clinically meaningful to accurate assessment of the nodule histology by CT scans with advanced deep learning algorithms. However, recent studies mainly focus on predicting benign and malignant nodules, lacking of model for the risk stratification of invasive adenocarcinoma. We propose an ensemble multi-view 3D convolutional neural network (EMV-3D-CNN) model to study the risk stratification of lung adenocarcinoma. We include 1075 lung nodules (≤30 mm and ≥4 mm) with preoperative thin-section CT scans and definite pathology confirmed by surgery. Our model achieves a state-of-art performance of 91.3% and 92.9% AUC for diagnosis of benign/malignant and pre-invasive/invasive nodules, respectively. Importantly, our model outperforms senior doctors in risk stratification of invasive adenocarcinoma with 77.6% accuracy [i.e., Grades 1, 2, 3]). It provides detailed predictive histological information for the surgical management of pulmonary nodules. Finally, for user-friendly access, the proposed model is implemented as a web-based system ( https://seeyourlung.com.cn ).